There is a high rate of alcohol use among HIV-infected individuals, and chronic alcohol use has been associated with high-risk sexual behavior, and reduced efficacy and adherence to antiretroviral therapy (ART). Collectively, these factors contribute to the transmission of HIV. In previous studies using the alcohol-fed rhesus macaques infected with Simian Immunodeficiency Virus (SIV), we have shown that chronic alcohol use is associated with higer levels of SIV in peripheral blood and more rapid disease progression. Additionally, we have shown that alcohol induced changes in the immunological profile of the gut mucosa, resulting in higher levels of SIV replication in the gut and peripheral blood, while others have identified alcohol-associated immunological changes in several tissues during acute SIV infection. These observations have led us to hypothesize that alcohol consumption will change the cellular milieu in the genital and rectal mucosa, providing an environment conducive to HIV infection, early replication, and shedding in genital secretions. Further, we hypothesize that increased early viral replication in these tissues will reduce the efficacy of ART in post-exposure prophylaxis and the longitudinal control of genital HIV shedding. These hypotheses will be addressed using the well-established SIV-rhesus macaque model for HIV disease, through the following specific aims. (1) Test the prediction that chronic alcohol consumption changes the cellular milieu and cytokine expression in the rectal mucosa of male macaques and the vaginal and cervical mucosa of female macaques. (2)Test the prediction that chronic alcohol exposure impacts the early dynamics of SIV infection and reduces the efficacy of post-exposure prophylaxis therapy. (3)Test the prediction that alcohol consumption increases SIV content in genital secretions, thereby increasing transmission risk. (4) Test the prediction that alcohol consumption reduces the ability of ART to suppress genital SIV shedding.